The t(1;14)(p22;q32) is a recurrent chromosomal rearrangement specific to the mucosa-associated lymphoid tissue (MALT) lymphomas that results in dysregulation of BCL10, an N-terminal caspase recruitment domain (CARD)-containing apoptosis signaling protein that normally promotes cell death and activates NF-kappaB. Although the mechanisms by which BCL10 induces death and NF-kappaB activity are poorly understood, proapoptosis by the protein appears due in part to binding and activation of procaspase-9 by the Ser/Thr-rich BCL10 C-terminus, which can undergo phosphorylation. In addition to being overexpressed, BCL10 cDNAs from t(1;14)-positive MALT tumors contain a variety of mutations, most resulting in truncations either in or C-termnal to the CARD. BCL10 CARD-truncation mutants are unable to induce death or activate NF-kappaB, while mutants with C-terminal truncations retain NF-kappaB activation but do not induce apoptosis. Because BCL10 promotes apoptosis, it may normally perform a tumor suppressor function. Loss of BCL10 proapoptosis through mutation should confer a survival advantage to cells, and constitutive NF-kappaB activation should provide both antiapoptotic and proliferative signals via its transcriptional targets. The relative importance of these events in tumorigenesis, or whether BCL10 mutants possess additional oncogenic properties, remain unknown. Aim 1a of this proposal seeks to improve understanding of the role of BCL10 in oncogenesis by elucidating its normal function in cell death regulation, using Bc110-null cells to identify the apoptotic pathways that require BCL10 activity and assessing the tumor suppressor capabilities of the protein in vivo. BCL10-interacting proteins and the functional effects of BCL10 C-terminal phosphorylation will be investigated in Aim 1b to further define the mechanisms that govern BCL10 cell death control. The transformation-enhancing properties of various BCL10 mutations will be assessed in Aim 2a, which asks whether biallelic inactivation of BCL10 is required for promotion of oncogenesis, and whether transdominant-inhibitory or transforming gain-of-function monoallelic mutations also contribute to tumor development. Finally, in Aim 2b, the effects of normal BCL10 or selected mutants on lymphoid development and transformation will be assessed in transgenic mice models to ensure the biologic relevance of observations made in previous Aims. Taken together, these studies should clarify the mechanisms by which BCL10 regulates apoptosis and the manner in which BCL10 mutations alter death regulation to promote oncogenesis.